HIV-1 infection of women is a relatively rare outcome of sexual exposure to HIV-1. The risk may vary for each woman, and it may also vary for the same woman during different exposures. Susceptibility is determined by a complex set of factors, including the amount and properties of the virus to which a woman is exposed, individual host genetic factors, as well as multiple modifiable biological cofactors present at the time of exposure. In this program project grant, we proposed to examine the mechanisms by which biological cofactors increase susceptibility of women to HIV-1. The proposed studies will include women in multiple high-risk groups: sex workers, pregnant/postpartum women and women in HIV-1 discordant relationships. Specifically, we will examine the role of: 1) pregnancy and the postpartum effects (Project 1);2) vaginal flora and specific bacterial infections (Project 2);3) innate immune factors, including as they relate to hormones and genital tract infections (Project 3);and 4) mucosal HIV-1 antibodies induced in response to repeated HIV-1 exposure (Project 4) on susceptibility to HIV-1 infection in women. For these studies, we will take advantage of cohort studies, collaborative partnerships and infrastructure developed by our research team, the Seattle/Kenya collaborative research group, over the past ~ 15 years. Our research group, which includes virologists, immunologists, bacteriologists, epidemiologist, statisticians and clinical scientists, has a long and productive history of collaboration, and is known for its focus on translational research in women. Here we will build on that foundation to conduct multiple collaborative projects within this program grant. We expect that each of these projects will draw on the expertise of others in the team, and in some cases, will include parallel studies that address synergistic biological questions in the same populations. RELEVANCE: Collectively, these studies are designed to provide a comprehensive picture of the biological factors that contribute to increased risk of HIV-1 infection in women. Such studies will be critical for understanding unique aspects of HIV-1 transmission in women, and for finding approaches to decrease transmission that consider issues that are relevant to women. PROJECT 1: Incidence, Timing and Cofactors that Contribute to the High Risk of HIV-1 Infection in Peri and Post Partum Women (Project Leader: John-Stewart, G) PROJECT 1 DESCRIPTION (provided by applicant): Pregnancy and the postpartum period have been associated with increased risk of HIV-1. In Africa, where both HIV-1 seroprevalence and fertility rates are high, the pregnancy/postpartum period may be one in which HIV-1 acquisition contributes substantially to HIV-1 in women. Pregnancy, delivery, and the postpartum period are associated with hormonal, genital mucosal, and genital flora changes that could predispose to acquisition of HIV-1. Project 1 will enroll 2,000 HIV-1 uninfected women identified during pregnancy and followed to 9 months postpartum to determine risk and cofactors of HIV-1 incidence. Women who acquire HIV-1 will be compared to women who do not in order to determine the role of genital coinfections, ulcers, delivery practice, lactation, partner characteristics, vaginal flora changes, HSV-2, genital innate immune factors, and systemic immune activation on HIV-1 transmission. In addition, changes in cofactors over the course of pregnancy and postpartum may influence susceptibility to HIV-1. Thus, in a subset of 100 women we will compare genital innate immune factors, and systemic cellular immune activation longitudinally during pregnancy, early postpartum, and later postpartum. These comparisons will provide opportunity to determine patterns of change in the genital tract during this dynamic period of change in women. In quantifying co-infections, mucosal innate immune responses, and systemic cellular immune activation, we will be able to determine interactions between these important determinants in 3 different but inter-related areas (co-infection, mucosal innate milieu, systemic cellular) that affect susceptibility to HIV-1. Project 1 will have scientific links to Project 2 (effects of changes in vaginal flora on HIV-1 transmission), Project 3 (which will involve cytokine profile analyses within women from the Project 1 cohort) and Project 4 (adaptive humoral mucosal responses in HIV-1 uninfected women with HIV-1 infected partners). Because of the complexity of the female genital ecosystem and the variety of factors that could alter susceptibility to HIV-1, each Project will focus on complementary factors that may modify transmission of HIV-1. Together, these will lead to a multi-faceted evaluation of transmission in women in different important groups of women at risk for HIV-1, (pregnant/postpartum, female sex workers, and discordant couples), that conceivably share some cofactors for HIV-1 susceptibility but are distinct in others. RELEVANCE: Women may be at increased risk for HIV-1 during and after pregnancy. This study will determine the risk of and cofactors for acquiring HIV-1 during and after pregnancy in a cohort of women in Kenya. Factors including genital infections and immunity will be assessed. These data will be directly relevant to developing appropriate strategies to protect women from HIV-1 during and after pregnancy.